Physiological amounts of glucocorticoid are crucial to maintain glucose homeostasis, blood pressure, immune function, neuronal excitability, well being and longevity in the face of diverse stressors. Gonadal sex steroids and gender govern key mechanisms that mediate the adaptive control of adrenocorticotropin (ACTH) and glucocorticoid secretion in laboratory animals. Studies of how sex steroids regulate the human corticotropic axis are fragmentary, contradictory, confounded by age effects and limited by experimental design and analyses. To address these fundamental knowledge deficits requires 4 investigative strategies, viz.: (1) addback of estradiol or testosterone during gonadal suppression by a GnRH-receptor antagonist with and without concomitant blockade of the estrogen or androgen receptor (ER and AR);(2) graded " imposition of delayed (integral) and rapid (rate-sensitive) cortisol negative feedback during adrenal steroidogenic blockade;(3) joint dose-dependent stimulation of ACTH secretion by human CRH and AVP;and (4) analytical reconstruction of altered tripartite (CRH, AVP and cortisol) regulation of ACTH secretion. The goal thereby is to parse the mechanistic bases of strong gender-associated distinctions in stress- adaptive control in healthy older adults according to 3 fundamental hypotheses: Hypothesis I. Estradiol will amplify dose-dependent actions of CRH and AVP, augment CRH/AVP synergy and mute delayed (integral) negative feedback by 3 strata of cortisol inhibition under constant mineralocorticoid availability. Estrogen's effects will be blocked by a selective ER antagonist. Hypothesis II. Testosterone will potentiate dose-dependent stimulation by CRH and AVP, increase 2- peptide synergy and attenuate delayed negative feedback by graded cortisol elevations. Testosterone's actions will be opposed by an aromatase inhibitor, and augmented by a specific AR antagonist. Hypothesis III. Estradiol and testosterone will relieve rapid (rate-sensitive) negative feedback by dose- varying pulses of cortisol in a manner reversed by an ER antagonist and aromatase inhibitor. The outcomes of these experiments should provide unique insights into the basic mechanisms that transduce gender distinctions in glucocorticoid regulation in the human. The expectation thereby is to foster novel diagnostic and interventional strategies to avert the sequelae of impaired or excessive stress adaptations in women and men. Public Summary. These studies will elucidate how female and male sex steroids govern gender-specific adaptations in stress-hormone secretion in humans. The goal is to unveil new ways to detect, prevent and treat abnormal stress-adaptive responses in aging, illness and disease.